METHOD OF PREPARING d1 6-PHENYL-2,3,5,6-TETRAHYDROIMIDAZO {8 2,1-b{9 -THIAZOLE HYDROCHLORIDE

ABSTRACT

A method of preparing 6-phenyl-2,3,5,6-tetrahydroimidazo( 2,1b)thiazole hydrochloride by reacting styrene oxide with ethyleneimine in a polar solvent to produce Alpha -phenyl-1aziridineethanol, treating this reaction product with thiocyanic acid and hydrochloric acid to obtain 2-imino- Alpha -phenyl-3thiazolidineethanol hydrochloride and reacting the 2-imino- Alpha -phenyl-3-thiazolidineethanol hydrochloride with thionyl chloride to obtain d1 3-( Beta -chlorophenethyl)-2-iminothiazolidine hydrochloride, treating this compound with aqueous alkali to obtain d1 3-( Beta -chlorophenethyl)-2-iminothiazolidine free base, and isomerizing the latter compound in the absence of alkali to obtain d1 6-phenyl-2,3,5,6-tetrahydroimidazo (2,1b)thiazole hydrochloride. The product is useful as an anthelmintic.

United States Patent Bullock July 25,1972

[73] Assignee: American Cyanamid Company, Stamford,

Conn.

[22] Filed: July 22, 1969 21 Appl. No.: 843,847

Related [1.8. Application Data [60] Continuation-in-part of Ser. No. 669,704, Sept. 22, 1967, abandoned, which is a division of Ser. No, 493,231, Oct. 5, 1965, abandoned.

2,606,155 8/1952 Hill ..252/149 FOREIGN PATENTS OR APPLICATIONS 34,860 12/1964 Germany ..260/306.7

OTHER PUBLICATIONS Dorn, Angfw. Chem., Vol. 76 1964), p. 301

Primary Examiner-Alex Mazel Assistant Examiner-R. J. Gallagher Att0rneyEmest Y. Miller [57] ABSTRACT A method of preparing 6-phenyl-2,3,5,6- tetrahydroimidazo[2,l-b]thiazole hydrochloride by reacting styrene oxide with ethyleneimine in a polar solvent to produce a-phenyl-l-aziridineethanol, treating this reaction product with thiocyanic acid and hydrochloric acid to obtain 2-iminoa-phenyl-3-thiazolidineethanol hydrochloride and reacting the 2-imino-a-phenyl-3-thiazolidineethanol hydrochloride with thionyl chloride to obtain d1 3-(B-chlorophenethyl)-2- iminothiazolidine hydrochloride, treating this compound with aqueous alkali to obtain d1 3-(B-chlorophenethyl)-2- iminothiazolidine free base, and isomerizing the latter compound in the absence of alkali to obtain d1 6-phenyl-2,3,5,6- tetrahydroimidazo [2,l-blthiazole hydrochloride. The product is useful as an anthelmintic.

4 Claims, No Drawings METHOD OF PREPARING D1 6-PI-IENYL-2,3,5,6- TETRAHYDROIMIDAZO [2, l -B]-THIAZOLE HYDROCHLORIDE This application is a continuation-inpart of my application Ser. No. 669,704, filed Sept. 22, 1967, now abandoned, which in turn is a division of application Ser. No. 493,231, filed Oct. 5, 1965, now abandoned.

SUMMARY OF THE INVENTION This invention relates to a method of preparing dl 6-phenyl- 2,3 ,5,6,-tetrahydroimidazo[ 2, l -b]thiazole hydrochloride, novel intermediates and methods of preparing the latter.

The d1 6-phenyl-2,3,5,6-tetrahydroimidazo[2,l-b]-thiazole hydrochloride prepared by the process of the present invention can be illustrated by the following formula:

In accordance with the process of the present invention d1 6- phenyl-2 ,3 ,5 ,6-tetrahydroimidazo[2 ,1 -b]thiazole hydrochloride is prepared by admixing, d1 3-(B-chlorophenethyl)-2-iminothiazolidine hydrochloride with an alkali metal or alkaline earth metal hydroxide or carbonate in the presence of water and a water immiscible organic solvent such as chlorinated hydrocarbon, a lower alkyl ester or an alkylene halide, but preferably the latter, at about ambient temperature and separating the organic phase. Solvents which are suitable for use in this reaction are chloroform, ethyl acetate, methylene chloride and ethylene chloride. The organic phase of the thus formed reaction mixtures contains dl 3-(B- chlorophenethyl)-2-iminothiazolidine free base. This free base can be recovered as such by evaporation of the solvent at or below ambient temperature or it can be converted directly in a single step to the dl 6-phenyl-2,3,5,6-tetrahydraimidazo[ 2,l-b]thiazole hydrochloride. In recovery of the free base evaporation is generally achieved under reduced pressure. If the solvent from the organic phase is not separated from the free base and the mixture is heated to between about 40 C. and 120 C. for a period of about 10 minutes to 3 hours, the d1 3-(B-chlorophenethyl)-2-iminothiazolidine is converted to dl @cH-om-rq a... i HN (III) @cm-om-rr 6-(phenyl-2 ,3 ,5 ,6-tetrahydroirn1;dazo[2 ,l -b] th i a;ole hydrochloride. This productcan then be recovered from the reaction mixture by titration of the hydrochloride which crystallizes.

Alternatively the hydrochloride salt of dl 6-phenyl 2,3,5,6-

tetrahydroimidazo[2,le-b]thiazole can be obtained by a step wise procedure involving (1) admixing d1 3-(B- chlorophenethyl)-2-iminothiazolidine hydrochloride with an alkali metal or alkaline earth metal hydroxide or carbonate in water and a water immiscible organic solvent as described above, (2) separating the organic phase from the thus formed mixture, (3) separating the solvent from said mixture while maintaining the temperature thereof below about 40 C. to obtain dl B-(B-chloro-phenethyl)-2-iminothiazolidine free base, (4) dissolving the thus formed free base in a lower alkyl alcohol having from one to four carbon atoms and preferably selected from the group consisting of methanol and ethanol, (5) heating the thus formed solution from about 40 to C. for about 10 minutes to 3 hours and (6) separating said lower alkyl alcohol from the hydrochloride salt of the product. In practice I have found that essentially optimum product yields can be obtained with this procedure when ethanol is employed as the solvent in step 4.

The d1 S-(B-chlorophenethyl)-2-iminothiazolidine hydrochloride which is cyclized to final product as described above is prepared from the corresponding 2-imino-a-phenyl-3 -thiazolidineethanol hydrochloride salt by reaction with thionyl chloride, phosphorus trichloride or phosphorus oxychloride. The reaction is usually carried out by mixing the intermediate with the halogenating agent and heating the mixture to a temperature within range of 40 to 120 C. for 5 minutes to 4 hours.

The dl 2-imino-a-phenyl-3thiazolidineethan0l is prepared as a salt by contacting a-phenyl-l-aziridineethanol with at least one molar equivalent of thiocyanic acid followed by treatment with a strong acid such as hydrochloric acid. The thiocyanic acid is usually prepared in situ by the acidification of any ammonium or metal thiocyanate salt, preferably sodium or potassium thiocyanates.

The a-phenyll-aziridineethanol can be prepared by a reaction of styrene oxide with ethyleneimine as described by Funke et al. Bull. Soc. Chim., France, 1953 (12013).

The process of the present invention starting with known reactants can be illustrated by the following flowsheet.

NEE

l S0 C1: (H)

Funke et al. as hereinbefore indicated. In accordance with the process of the invention, this compound can then be transformed into the compound of formula (II) by reaction thereof V 1 V 4 2,3,5,6-tetrahydroimidazo-[ 2, l-blthiazole (VI).

The compound of the present invention was tested by standard parasitological procedures for evaluating anthelmintic hydrochloride with about 1 mole equivalent of thiocyanic acid which can be 5 yr -r in case? th critical" test in which the prepared bly the iaiclidigcatrign of any ammonium or metal thioagof 3 :2 gm mzzl id m btre g e rfzilowlgf :reatmtelnt cyanate sa t, wit y me oric acid. When the com und of P e o 0 W0 P n v e formula (II) is treated with about 1 molar equival eilt of a sum of those eliminated and thus; p s a p y. and strong acid, such as hydrochloric, it is immediately converted (2) the m winch f average to the Z-iminothiazolidine alcohol of formula (III). The forma- 10 of worms all 'i gt i t fi at tion of (III) from (11) occurs rapidly at pH l.53. The formanecropsy sever i rca t e avg-age ion of both (In and (III) are preferably carried out in 310w" numbenpresent 1n similarly infected but untreated anlrnals. Dependlng upon the host specles and the partlcular helmlnth alkanol of one to four carbon atoms. The compound (II!) can h n be convened to com und (IV) b coma ti (1) will studled the infections were experimentally Induced or in some ha] r l 15 cases naturally acquired. The tests showed that dl-2,3,5,6- hmnyl 9 9" "F as tetrahydro-o-phenyl-imidazo[2,l-b]thiazole hydrochloride is Phosphorus mchlonde or ltm qfq yf qfl 'i wluch highly active against a very broad spectrum of nematode known to transform alcohols to halides. This reaction is run at parasites f mammals and birds at low dosages and by varied a temPeraml'e betwfen and when the compound routes of administration. The following Table gives illustrative f f '3? Q g a} FPlEQF mEE W 9)". EPQ representative results obtained in testing the above described C., it 18 Imm di y n f m lntO i free base imidazothiazole, and is not intended to be limiting in regard to reprmm y when this free base 13 heated to a dose ranges, routes of administration, or species of netemperature be n about 4 n 1 in a Solvent in the matodes. Data refer to adult helminths unless otherwise inabsence of base, it is isomerized to yield directly 6-phenylfl ted,

TABLE Approximate percent average Doses mg./kg. (or other) Route of administration efficacy Species of adult nematode 1 30 Oral gavage 100 SuphacimAspiculuri-n 25.. (1 -100 Nematospiroilies dubius.

80 Nematospimidee dubius.

(0.1% in feed) Drug-diet 38 fg ggg ggf Sheep:

3.75-10 Oral drench Haemonchus contort'us.

3.76-10. d Nematodirus sp.

Trichoetro'ngylus azel'.

Ostertagle circumcincta.

Ostertaaia circumcincta.

gichoatronqylus colubrl'forml's and T. vl'trinua.

T.c. and T.v. Nemqtodirus op. H .c. larvae.

T.c. larvae.

themes..."

2.5-10 Oral drench 7.6-20-.. do

Swine:

5 Oral capsule or feed l0. In drinking water In drinking water or oral capsule" lndrinkingwatenuu l In e slp nt nliqe x- 10 o Chicken: 80 In drinking water Ostertapi sp. Cooperia sp. Nemalodirus sp. Oesophagoatommn 31). 11.1).

()stertrlqia .vp. Cooperiu .vp. Nemalodims .91). Gas. .xp. Bunoatomum .11). H4).

T. aui.

Ostertaqla sp. Cooperz'a s12. Nematodirus lip.

Aacaris mum. Ascarl's aumn. Metaatrongylus sp. Oesophagoatomum 8]). Ascaris lmum larvae.

Ancylastoma caninum. 'I'ozacara canl'a. Clozascaria leonina. Ascarl'dz'a galli larvae.

- Unless otherwise indicated.

DETAILED DESCRIPTION The following examples describe in detail the preparation of intermediates and final product of this invention.

' EXAMPLE 1 d 1 a-Phenyll -Aziridineethanol To a solution of 43.0 grams (1.0 mole) of ethyleneimine and 60.0 grams (0.5 mole) of styrene oxide is added 3 drops of water and 0.2 grams of potassium hydroxide. The mixture is heated at reflux for l a hours. Distillation of the crude product gives 55.6 grams (68%) of the crystalline product. Recrystallization gives pure a-phenyl-l-aziridineethanol with melting point 7476 C.

EXAMPLE 2 dl a-Phenyll -Aziridineethanol A solution of 60.0 grams (0.5 mole) of styrene oxide, 50 ml. of ethanol, and 0.2 grams of potassium hydroxide is prepared. To this solution is added 25.9 grams (0.6 mole) of ethyleneimine in portions. The mixture is maintained at 2930 C. for 20 minutes, and then is heated at reflux for 30 minutes. The solvent is removed under reduced pressure to provide the crude product. Addition of petroleum ether to the residue gives 8.5 grams of product with melting point 53-63 C. Distillation of the remaining oil gives an additional 30.7 grams of product, melting point 56-65 C., the total yield is 48%.

EXAMPLE 3 d 1 a-Phenyl- 1 -aziridineethanol 98-105 C., melting point 5773 C.;:202.8 g. boiling point 98 C., melting point 57-7 1 C. (lit. (4) boiling point 1 l61 1 7/0.06 mm., melting point 73 C. The melting points are determined on crystals dried on filter paper.

EXAMPLE 4 d1 2-lmino-a-Phenyl-3-Thiazolidineethanol Hydrochloride To a solution of 1.17 grams (0.012 mole) of potassium thiocyanate in 10 ml. of ethanol is added 0.011 mole of hydrogen chloride in 3 ml. of ethanol. The mixture is warmed to 50 C., cooled, and the precipitated potassium chloride filtered off. The filtrate, which contains 0.011 mole of thiocyanic acid, is added to a solution of 1.63 grams (0.01 mole) of a-phenyl-laziridineethanol at a rate sufficient to maintain the reaction temperature at 3035 C. After the addition of the thiocyanic acid is complete, the product d1 2-[(B-hydroxyphenethyl)amino]-ethyl thiocyanate is treated with a solution of 0.015 mole of hydrogen chloride in 5 ml. of ethanol. Removal of the solvent at a reduced pressure gives the product, melting point l96l99 C., in a 95% yield. Recrystallization from ethanol provides the pure product, with melting point 1 98-200 C.

EXAMPLE 5 d1 2-lmino-a-phenyl- 3-triolzolidineethanol Hydrochloride To a solution of 87.2 g. 1.1 mole) of sodium thiocyanate in 1,700 ml. of isopropanol is added 163.2 g. 1.0 mole) of aphenyl-l-aziridineethanol in 700 ml. of isopropanol and 163 ml. of 12 N hydrochloric acid during 0.5 hr., while maintaining the apparent pH of l.5-3.0 as read with a glass electrode of a pH meter. After an additional 20 minutes, 20 ml. of 12 N hydrochloric acid (total of 2.2 moles) is added. The mixture is filtered and air dried to give 269 g. of sodium chloride and product. Concentration of the filtrate gives 68.8 g., melting point 199201 C. of the pure crystalline product. The salt contaminated product is treated with 150 ml. of water, filtered, washed with ether and dried to give 109.1 g. of product. melting point 203-205 C. A total of 177.9 g. (69%, based on axiridine) of product is obtained.

EXAMPLE 6 d1 Z-Imino-a-phenyl-3-thiazolidineethanol Hydrochloride The crude product from the reaction of 1.0 mole of ethylenimine with 0.50 mole of styrene oxide is divided into 2 equal portions. From one a total of 23.95 g. (58%) of crystalline a-phenyl-l-aziridineethanol is obtained by vacuum distillation. The other half is reacted with thiocyanic acid without purification.

A warm mixture of 26.7 g. (0.275) mole) of potassium thiocyanate in 250 ml. of ethanol is treated with 53 g. of a methanolic solution of hydrogen chloride (0.25 mole). The precipitated potassium chloride is filtered, and washed with ethanol to provide the thiocyanic acid solution.

To the stirred solution of thiocyanic acid is added a solution of the crude a-phenyl-l-aziridineethanol in 250 ml. of ethanol at a rate sufficient to keep the reaction temperature at 3035 C. After the aziridine addition is complete, 72 g. of a methanolic solution of hydrogen chloride (0.35 mole) is added and the solution stirred for 1.5 hours at room temperature. An additional 0.05 mole of hydrogen chloride in 10 g. of ethanol is added, and the reaction heated at 35-40 C. for 0.5 hour. It is then allowed to proceed at room temperature for 2.5 days. Essentially no change is evident (by infrared) from the further reaction at room temperature, but crystallization of the product did occur. The mixture is concentrated at reduced pressure to ca. ml., filtered, washed with ethanol and dried to give 27.1 g. of white crystals, melting point l98-200 C. The yield is 42% (based on styrene oxide) or 71% (based on dl a-phenyl-l-aziridineethanol).

EXAMPLE 7 d1 3- 3-(B-Chlorophenethyl )-2-lminothiozoladine Hydrochloride To a solution of 2.25 grams (0.009 mole) of 2-imino-aphenyl-3-thiazolidineethanol hydrochloride in 50 ml. of chloroform is added 3 ml. of thionyl chloride. The mixture is refluxed for 30 minutes, and the solvent removed under pressure to give 1.93 grams of solid product.

EXAMPLE 8 d1 3-(fi-Chlorophenethyl)-2-lminothiazolidine Hydrochloride To a stirred slurry of 40.0 g. (0.154 mole) of Z-imino-aphenyl-3-triazolidineethanol hydrochloride and 62 ml. of methylene chloride is added 17 mi. (28.4 g., 0.238 mole) of thionylchloride over a period of 2-3 minutes (a brief, slightly exothermic reaction occurred). After 45 minutes at room temperature the reaction is complete, as shown by thin layer chromatography (TLC) with acetonitrile:ammonium hydroxide 98:2 (v/v). The reaction mixture, a very thick slurry, is filtered, washed with methylene chloride and ether, and dried. The crude product weighs 39.0 g. (91%), melting point l78-182 C. and ca. 240. Recrystallization of the product from ethanol gives 25.3 g. (59%) of white crystals, melting point 245-246 C.

7 a TPLES dl 2-Phenyl-2,3,5,6-Tetrahydroimidazo[Tetrahydroimidazo [2,l-b]thiazolium Chloride One gram (0.036 mole) of 3-(B-chlorophenethyl)-2- iminothlazolidine hydrochloride is partitioned between 50 ml. of ethylacetate and a solution of 2.34 g. (0.017 moles) of potassium carbonate in 32 ml. of water. The ethylacetate layer is separated and heated at reflux temperature for 2 15 hours. The precipitate of 6-phenyl-2,3,5,6-tetrahydroimidazo[2,1- b]-thiazolium chloride is collected by filtration and recrystallized from absolute ethanol to yield 0.3 g. of pure product, melting point257-25 9 C.

EXAMPLE [0 dl 6-Phenyl-2,3,5,6-tetrahydroimidazo[2,l-b]thiazolium Chloride To a mixture of 1.38 g. (5.0 mmoles) of 3-(B- chlorophenethyl)-2-iminothiazolidine hydrochloride (IV) in 20 ml. of water and 25 ml. of methylene chloride is added a solution of 1.38 g. mmoles) of potassium carbonate in 5 ml. of water. The mixture is shaken, the layers separated, and the combined organic layers are washed with water and dried over magnesium sulfate. Removal of the solvent under reduced pressure gives a yellow oil. It is dissolved in 60 ml. of ethanol and heated at reflux for 45 minutes, then allowed to stand at 25 C. for 0.5 hours. Evaporation of the solvent at reduced pressure, and treatment of the residue with ether gives 1.17 g. (94%) of light yellow crystals, melting point 249-254 C.

1 claim:

1. A method for the preparation of dl 6-phenyl-2,3,5,6- tetrahydroimidazo[2,l-b]thiazole hydrochloride comprising the steps of (l) admixing dl 3-(fi-chlorophenethyl)-2- iminothiazolidine hydrochloride with an alkali metal or alkaline earth metal hydroxide or carbonate in water and a water immiscible organic solvent selected from the group consisting of chlorinated hydrocarbons, lower alkyl esters and alkylene halides while maintaining the temperature of said mixture below about 40 C., (2) separating the organic phase from the thus formed mixture, (3) removing the solvent while maintaining the temperature below about 40 C., (4) dissolving the residue obtained from the above separation in a lower alkyl alcohol having from one to four carbons atoms, (5) heating the thus formed solution to a temperature of from about 40 to C. for about 10 minutes to 3 hours and (6) separating the lower alkyl alcohol from said reaction mixture to give the product.

2. A method according to claim 1, where in the water immiscible organic solvent of step (1) is selected from the group consisting of chloroform, methylene chloride, ethylene chloride and ethyl acetate and wherein the lower alkyl alcohol step (4) is selected from the group consisting of methanol and ethanol.

3. A method according to claim 1, wherein the water immiscible organic solvent is selected from the group consisting of methylene chloride and ethylene chloride and the lower alkyl alcohol is ethanol.

4. A method for preparing dl 6-phenyl-2,3,5,6- tetrahydroimidazo[2,l-b]thiazole hydrochloride comprising the steps of (1) heating styrene oxide with ethyleneimine in the presence of a polar solvent to obtain dl-a-phenyl-laziridineethanol, (2) treating said dl-a-phenyl-laziridineethanol with approximately an equal molar amount of thiocyanic acid or an alkali metal thiocyanate in the presence of an organic solvent and thereafter treating the thus prepared reaction mixture with from about l-2 molar equivalents of hydrochloric acid to obtain dl 2-imino-a-phenyl-3- thiazolidineethanol hydrochloride, (3) treating the above said thiazolidineethanol hydrochloride with a chlorinating agent selected from the group consisting of thionyl chloride,

phosphorus trichloride and phosphorus oxychloride at a tem- I perature between about 40 to 120 C. for 5 minutes to 4 hours to obtain dl S-(B-chlorophenethyl)-2-iminothiazolidine hydrochloride, (4) treating the latter hydrochloride with an aqueous solution of an alkali metal or alkaline earth metal hydroxide or carbonate and a water immiscible solvent selected from the group consisting of chlorinated hydrocarbons, lower esters and alkylene halides, and separating the organic phase, (5) removing the solvent while maintaining the temperature below about 40 C., (6) dissolving the residue obtained from the above separation in a lower alkyl alcohol having from one to four carbon atoms, and (7) heating said alcoholic solution to a temperature between about 40 to 120 C. to obtain d1 6-phenyl-2,3,5,6-tetrahydroimidazo[2,1- blthiazole hydrochloride.

ll t ll 

2. A method according to claim 1, where in the water immiscible organic solvent of step (1) is selected from the group consisting of chloroform, methylene chloride, ethylene chloride and ethyl acetate and wherein the lower alkyl alcohol step (4) is selected from the group consisting of methanol and ethanol.
 3. A method according to claim 1, wherein the water immiscible organic solvent is selected from the group consisting of methylene chloride and ethylene chloride and the lower alkyl alcohol is ethanol.
 4. A method for preparing dl 6-phenyl-2,3,5,6-tetrahydroimidazo(2,1-b)thiazole hydrochloride comprising the steps of (1) heating styrene oxide with ethyleneimine in the presence of a polar solvent to obtain d1- Alpha -phenyl-1-aziridineethanol, (2) treating said d1- Alpha -phenyl-1-aziridineethanol with approximately an equal molar amount of thiocyanic acid or an alkali metal thiocyanate in the presence of an organic solvent and thereafter treating the thus prepared reaction mixture with from about 1-2 molar equivalents of hydrochloric acid to obtain d1 2-imino- Alpha -phenyl-3-thiazolidineethanol hydrochloride, (3) treating the above said thiazolidineethanol hydrochloride with a chlorinating agent selected from the group consisting of thionyl chloride, phosphorus trichloride and phosphorus oxychloride at a temperature between about 40* to 120* C. for 5 minutes to 4 hours to obtain d1 3-( Beta -chlorophenethyl)-2-iminothiazolidine hydrochloride, (4) treating the latter hydrochloride with an aqueous solution of an alkali metal or alkaline earth metal hydroxide or carbonate and a water immiscible solvent selected from the group consisting of chlorinated hydrocarbons, lower esters and alkylene halides, and separating the organic phase, (5) removing the solvent while maintaining the temperature below about 40* C., (6) dissolving the residue obtained from the above separation in a lower alkyl alcohol having from one to four carbon atoms, and (7) heating said alcoholic solution to a temperature between about 40* to 120* C. to obtain d1 6-phenyl-2, 3,5,6-tetrahydroimidazo(2,1-b)thiazole hydrochloride. 